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Fármacos antiinflamatorios no esteroideos orales (AINE) para el dolor por cáncer en adultos

Appendices

Appendix 1. Search strategy for CENTRAL (via CRSO)

  1. MESH DESCRIPTOR Anti‐Inflammatory Agents, Non‐Steroidal EXPLODE ALL TREES (15201)

  2. (NSAID* or "non‐steroidal anti‐inflammatory drug*"):TI,AB,KY (3754)

  3. ((aceclofenac or acemetacin or azapropazone or celecoxib or ketoprofen or dexketoprofen or diclofenac or dipyrone or etodolac or etoricoxib or fenbufen or fenoprofen or flurbiprofen or ibuprofen or Indomet?acin or “mefenamic acid” or meloxicam or nabumetone or naproxen or piroxicam or sulindac or tenoxicam or tiaprofenic acid)):TI,AB,KY (14109)

  4. (Apazone or Ketoprofen or Diclofenac or Etodolac or Fenoprofen or Flurbiprofen or Ibuprofen or Indomethacin or Mefenamic Acid or Naproxen or Piroxicam or Sulindac):MH (5867)

  5. #1 OR #2 OR #3 OR #4 (23883)

  6. MESH DESCRIPTOR Neoplasms EXPLODE ALL TREES (48784)

  7. (neoplasm* or malignan* or tumour* or tumor* or cancer* or carcinoma*):TI,AB,KY (112035)

  8. #6 OR #7 (117073)

  9. MESH DESCRIPTOR Pain EXPLODE ALL TREES (34252)

  10. (pain* or nocicept* or neuropath*):TI,AB,KY (99145)

  11. #9 OR #10 (104045)

  12. #5 AND #8 AND #11 (548)

Appendix 2. Search strategy for MEDLINE (via Ovid)

  1. exp Anti‐Inflammatory Agents, Non‐Steroidal/ (181078)

  2. (NSAID* or "non‐steroidal anti‐inflammatory drug*".tw. (24689)

  3. Apazone/ or Ketoprofen/ or Diclofenac/ or Etodolac/ or Fenoprofen/ or Flurbiprofen/ or Ibuprofen/ or Indomethacin/ or Mefenamic Acid/ or Naproxen/ or Piroxicam/ or Sulindac/ (51468)

  4. (aceclofenac or acemetacin or azapropazone or celecoxib or ketoprofen or dexketoprofen or diclofenac or dipyrone or etodolac or etoricoxib or fenbufen or fenoprofen or flurbiprofen or ibuprofen or Indomet?acin or “mefenamic acid” or meloxicam or nabumetone or naproxen or piroxicam or sulindac or tenoxicam or tiaprofenic acid).tw (66755)

  5. 1 or 2 or 3 or 4 (202029)

  6. exp Neoplasms/ (2963191)

  7. (neoplasm* or malignan* or tumour* or tumor* or cancer* or carcinoma*).mp. (3245993)

  8. 5 or 6 (3579379)

  9. exp Pain/ (349136)

  10. (pain* or nocicept* or neuropath*).mp. (682211)

  11. 8 or 9 (756162)

  12. randomized controlled trial.pt. (456758)

  13. controlled clinical trial.pt. (93340)

  14. randomized.ab. (348554)

  15. placebo.ab. (171262)

  16. drug therapy.fs. (1967607)

  17. randomly.ab. (239695)

  18. trial.ab (363855)

  19. 12 or 13 or 14 or 15 or 16 or 17 or 18 (2663271)

  20. 5 and 8 and 11 and 19 (1736)

Appendix 3. Search strategy for Embase (via Ovid)

  1. exp Anti‐Inflammatory Agents, Non‐Steroidal/ (533081)

  2. (NSAID* or "non‐steroidal anti‐inflammatory drug*").tw. (42811)

  3. (aceclofenac or acemetacin or azapropazone or celecoxib or ketoprofen or dexketoprofen or diclofenac or dipyrone or etodolac or etoricoxib or fenbufen or fenoprofen or flurbiprofen or ibuprofen or Indomet?acin or mefenamic or meloxicam or nabumetone or naproxen or piroxicam or sulindac or tenoxicam or tiaprofenic acid).tw. (94288)

  4. Apazone/ or Ketoprofen/ or Diclofenac/ or Etodolac/ or Fenoprofen/ or Flurbiprofen/ or Ibuprofen/ or Indomethacin/ or Mefenamic Acid/ or Naproxen/ or Piroxicam/ or Sulindac/

  5. 1 or 2 or 4 (545302)

  6. exp Neoplasms/ (4021384)

  7. (neoplasm* or malignan* or tumour* or tumor* or cancer* or carcinoma*).mp. (4471451)

  8. 6 or 7 (4961554)

  9. exp Pain/ (1138211)

  10. (pain* or nocicept* or neuropath*).mp. (1310694)

  11. 9 or 10 (1578116)

  12. (random* or factorial* or crossover or "cross‐over" or cross‐over).tw. (1253752)

  13. (placebo* or (doubl* adj blind*) or (singl* adj blind*)).tw. (331489)

  14. (assign* or allocat*).tw. (420484)

  15. crossover procedure/ (55966)

  16. double‐blind procedure/ (142603)

  17. Randomized Controlled Trial/ (488123)

  18. 12 or 13 or 14 or 15 or 16 or 17 (1675367)

  19. 5 and 8 and 11 and 18 (2529)

Appendix 4. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Higgins 2011).

  1. High: randomised trials; or double‐upgraded observational studies.

  2. Moderate: downgraded randomised trials; or upgraded observational studies.

  3. Low: double‐downgraded randomised trials; or observational studies.

  4. Very low: triple‐downgraded randomised trials; or downgraded observational studies; or case series/case reports.

Factors that may decrease the quality level of a body of evidence are:

  1. limitations in the design and implementation of available studies suggesting high likelihood of bias;

  2. indirectness of evidence (indirect population, intervention, control, outcomes);

  3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

  4. imprecision of results (wide confidence intervals);

  5. high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

  1. large magnitude of effect;

  2. all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

  3. dose‐response gradient.

Appendix 5. Summary of results in individual studies: efficacy

Study

Intervention

Participants with at least 50% and at least 30% reduction in pain

Participants with pain no worse than mild

Participants with PGIC of much improved or very much improved

Other measures of pain intensity or pain relief

NSAID versus NSAID

Gallucci 1992

Nimesulide 2 x 200 mg daily, n = 34
Naproxen 2 x 500 mg daily, n = 34

No data

No data

No data

In participants completing 2 weeks (43)
Integrated Score reduced by 65% with nimesulide and 70% with naproxen. No significant difference between groups

Minotti 1989

Diclofenac Na (Voltaren) 4 x 50 mg daily, n = 33
Nefopam 4 x 60 mg daily, n = 33
Aspirin + codeine 4 x 640 mg + 40 mg daily, n = 33

Responder defined as ≥ 50% PI reduction or PI ≤ 40/100

But individual data given only for pain ≥40/100 mm on day 2

No data

Mean PR:
Diclofenac 20/100
Nefopam 18/100
Codeine + aspirin 19/100

Mohammadinejad 2015

Celecoxib 2 x 200 mg daily, n = 28 (26)
Diclofenac 2 x 50 mg daily, n = 28 (26)

No data

No data

No data

No difference between groups at baseline or end of study

Mean PI reduced from about 60/100 to about 45/100

Pannuti 1999

Ketorolac 3 x 10 mg daily
Diclofenac 50 mg 3 x 50 mg daily

Cross‐over, n = 137

No data

No data

PGE "good or complete":
Ketorolac 34/128
Diclofenac 33/129

PGE "moderate, good or complete":
Ketorolac 83/128
Diclofenac 74/129

15 participants had relief with ketorolac but not diclofenac; 14 participants had relief with diclofenac but not ketorolac

Rodriguez 2003

Dexketoprofen trometamol 4 x 25 mg daily, n = 57
Ketorolac 4 x 10 mg daily, n = 58

No data

PI < 30/100 at end of study:
Dexketoprofen 31/56
Ketorolac 27/57

Overall efficacy of medication quite or very effective:
Dexketoprofen 76%
Ketorolac 67%

PID ≥ 20/100 at end of study:
Dexketoprofen 42/56
Ketorolac 37/57

Toscani 1994

Ketorolac 4 x 10 mg daily, n = 50
Diclofenac Na 3 x 50 mg daily, n = 50

No data

No data

Pain Integrated Score halved in first week (mostly by 1 day) from about 40 to 20

Patients remaining on treatment > 14 days:
Ketorolac 20/50
Diclofenac 15/50

Mean time to step II:
Ketorolac 58 (SD 46, median 41) days
Diclofenac 33 (SD 15, median 27) days
NSD

Turnbull 1986

Naproxen 2 x 500 mg daily, n = 28
Aspirin 6 x 600 mg daily, n = 28

No data

No data

No data

PI reduced by about 15/100 in both groups, with large SDs

Ventafrida 1990a

Naproxen Na 2 x 550 mg daily, n = 50
Diclofenac Na 2 x 100 mg daily n = 50

No data

No data

No data

Mean Integrated Pain Score decreased by ˜25 points in both groups (> halved) to 15.7 with naproxen and 17 with diclofenac

[judged equivalent to < 35/100 on VAS]

In participants who switched to step II
Treatment for ≥ 14 days:
Naproxen 14/33
Diclofenac 8/32

Yalçin 1998

Diflunisal 2 x 500 mg daily
Dipyrone 3 x 500 mg daily

Cross‐over, n = 50

No data

No data

No data

Mean reduction in PI (scale 0 ‐ 10):
Diflunisal 4.7 (SD 3.1)
Dipyrone 3.3 (SD 2.9)

NSAID versus opioid

Carlson 1990

Ketorolac tromethamine 4 x 10 mg daily, n = 34
Paracetamol + codeine 4 x 600 mg/60 mg daily, n = 40

No data

No data

No data

Mean daily PR greater for combination than ketorolac over 7 days; statistically significant for days 2 and 4

Mean daily medication ratings similar ‐ no difference between treatments

Minotti 1989

See above

Rodriguez 1994

Dipyrone 3 x 1000 mg daily, n = 41
Dipyrone 3 x 2000 mg daily, n = 38
Morphine 6 x 10 mg daily, n = 42

Dose could be increased on day 4: up to 3 x 2000 mg dipyrone, and 6 x 30 mg morphine

≥ 50% pain improvement:
Day 3
Dipyrone 3000 mg 5% (2/41)
Dipyrone 6000 mg 8% (3/38)
Morphine 60 mg 25% (10/42)
Day 5
Dipyrone 3000 mg 12% (5/41)
Dipyrone 6000 mg 48% (15/38)
Morphine 60 mg 39% (20/42)

No data

No data

Decrease in mean PI on day 7:
Dipyrone 3000 mg 30.9 (SD 32.6)
Dipyrone 6000 mg 39.8 (SD 28.6)
Morphine 60 mg 42.6 (SD 32.9)

n: number of participants in treatment arm; Na: sodium; PGE: Patient Global Evaluation; PGIC: Patient Global Impression of Change; PI: pain intensity; PID: pain intensity difference; PR: pain relief; SD: standard deviation

Appendix 6. Summary of results in individual studies: rescue medication, adverse events, withdrawals

Study

Intervention

Use of rescue or breakthrough medication

Participants with any adverse event and serious adverse events

Participants with specific adverse events

Withdrawals

NSAID versus NSAID

Gallucci 1992

Nimesulide 2 x 200 mg daily, n = 34
Naproxen 2 x 500 mg daily, n = 34

No data

Any AE: no data

SAE: none specifically reported

Deaths:
Nimesulide 5/34
Naproxen 9/34

Somnolence:

Nimesulide 6/34

Naproxen 6/34

Dyspepsia:

Nimesulide 18/34

Naproxen 12/34

AE:
Nimesulide 4/34
Naproxen 6/34
(gastric pain, haemorrhage, vomiting)

Participant refusal or lost to follow‐up:
Nimesulide 3/34
Naproxen 1/34

Shift to step II:
Nimesulide 22/34
Naproxen 18/34

Minotti 1989

Diclofenac Na (Voltaren) 4 x 50 mg daily, n = 33
Nefopam 4 x 60 mg daily, n = 33
Aspirin + codeine 4 x 640 mg + 40 mg daily, n = 33

No data

Any AE: no data

SAE: none reported

Somnolence:

Diclofenac 0/33

Nefopam 2/33

Aspirin + codeine 4/33

Dyspepsia:

Diclofenac 0/33

Nefopam 3/33

Aspirin + codeine 1/33

All cause:
Diclofenac 23/33
Nefopam 29/33
Codeine + aspirin 21/33

AE:

Diclofenac 1/33
Nefopam 5/33
Codeine aspirin 6/33

LoE:
Diclofenac 16/33
Nefopam 14/33
Codeine + aspirin 10/33

LoE + AE: Nefopam 1/33

Participant refusal: Nefopam 2/33

Exclusion criteria occurred during trial:
Diclofenac 4/33
Nefopam 4/33
Codeine + aspirin 1/33

Other:
Diclofenac 2/33
Nefopam 3/33
Codeine + aspirin 4/33

Mohammadinejad 2015

Celecoxib 2 x 200 mg daily, n = 28 (26)
Diclofenac 2 x 50 mg daily, n = 28 (26)

No data

Any AE: no data

SAE: none

Dyspepsia:

Celecoxib 2/28

Diclofenac 5/28

AE: none

2 participants in each group withdrew before 3 weeks because depression worsened from moderate to severe

Pannuti 1999

Ketorolac 3 x 10 mg daily
Diclofenac 50 mg 3 x 50 mg daily

Cross‐over, n = 137

No data

Any AE:
Ketorolac 10/128 (8% )
Diclofenac 7/129 (5%)
Most mild or moderate

SAE: none reported

Dyspepsia:

Ketorolac 6/128

Diclofenac 5/129

All cause:

Ketorolac 10/128
Diclofenac 15/129

(due to intolerance [AE] 2, LoE 23 ‐ group not given)

Rodriguez 2003

Dexketoprofen trometamol 4 x 25 mg daily, n = 57
Ketorolac 4 x 10 mg daily, n = 58

Dexketoprofen 71%
Ketorolac 72%

Median number of tablets (25 ‐ 75 percentile)
Dexketo 3 (0 ‐ 10)
Ketorolac 6 (0 ‐ 12)

Any AE:
Dexketoprofen 19/57
Ketorolac 20/58

[Note, these data from text. Data in table 6 indicated dexketoprofen 12 and ketorolac 19 ‐ but 'treatment‐related'. Unable to reconcile]

Most of mild to moderate intensity

SAE:
Dexketoprofen 2/57
Ketorolac 2/58

Dyspepsia:

Dexketoprofen 3/57

Ketorolac 3/58

1 participant in each group had missing post‐baseline efficacy data

AE:
Dexketoprofen 1/57 (death due to progression of disease)
Ketorolac 5/58

LoE:
Dexketoprofen 1/57
Ketorolac 6/58

Concomitant disease/other treatments:
Dexketoprofen 3/57
Ketorolac 2/58

Toscani 1994

Ketorolac 4 x 10 mg daily, n = 50
Diclofenac Na 3 x 50 mg daily, n = 50

No data

Any "symptoms" of high intensity

1st week:

Ketorolac 20/50

Diclofenac 26/50

2nd week:

Ketorolac 15/50

Diclofenac 21/50

Somnolence:

Ketorolac 2/50

Diclofenac 4/50

Anorexia:

Ketorolac 1/50

Diclofenac 6/50

Dry mouth:

Ketorolac 4/50

Diclofenac 5/50

Dyspepsia:

Ketorolac 2/50

Diclofenac 2/50

AE: "none due to drug treatment"

Compliance issues:
Ketorolac 4/50
Dicofenac 7/50

Participant request/lost to follow‐up:
Ketorolac 3/50
Dicofenac 3/50

Turnbull 1986

Naproxen 2 x 500 mg daily, n = 28
Aspirin 6 x 600 mg daily, n = 28

No data

"No side effects were reported and haematological and biochemical parameters did not significantly alter during the study"

SAE: 2 deaths not related to study drugs

None

All cause: 5/28

LoE: 1 with naproxen

Particiapnt decision: 2 due to number of tablets to be taken

Ventafrida 1990a

Naproxen Na 2 x 550 mg daily, n = 50
Diclofenac Na 2 x 100 mg daily n = 50

No data

Any AE: no data

Deaths:

Naproxen 2/50
Diclofenac 2/50

Somnolence:

Naproxen 4/50

Diclofenac 10/50

Dry mouth:

Naproxen 6/50

Diclofenac 8/50

Dyspepsia:

Naproxen 6/50

Diclofenac 8/50

All cause:
Naproxen 17/50
Diclofenac 18/50

AE:
Naproxen 1/50 (GIH)
Diclofenac 0/50

Start of other treatment:
Naproxen 11/50
Diclofenac 12/50

Lost to follow‐up
Naproxen 2/50
Diclofenac 3/50

Participant decision:
Naproxen 1/50

Pain resolved:
Diclofenac 1/50

Move to step II
LoE:
Naproxen 25/50
Diclofenac 25/50
AEs:
Naproxen 4/50
Diclofenac 5/50
Both:
Naproxen 4/50
Diclofenac 2/50

Yalçin 1998

Diflunisal 2 x 500 mg daily
Dipyrone 3 x 500 mg daily

Cross‐over, n = 50

No rescue medication allowed

Any AE: no data

SAE: 1 death due to disseminated malignancy (treatment at time not given)

Somnolence:

Diflunisal 0/50

Dipyrone 2/50

Anorexia:

Diflunisal 2/50

Dipyrone 1/50

Dyspepsia:

Diflunisal 2/50

Dipyrone 1/50

AE: none

2 participants lost to follow‐up

NSAID versus opioid

Carlson 1990

Ketorolac tromethamine 4 x 10 mg daily, n = 34
Paracetamol + codeine 4 x 600 mg/60 mg daily, n = 40

No data

Any AE:
Ketorolac 21/34
Paracetamol + codeine 19/40

SAE: none reported

Somnolence:

Ketorolac 1/34

Paracetamol + codeine 3/40

Anorexia:

Ketorolac 1/34

Paracetamol + codeine 1/40

Dry mouth:

Ketorolac 0/34

Paracetamol + codeine 2/40

Dyspepsia:

Ketorolac 5/34

Paracetamol + codeine 4/40

All cause:
Ketorolac 17/34
Paracetamol + codeine 27/40

LoE:
Ketorolac 8/34
Paracetamol + codeine 7/40

AE:
Ketorolac 5/34
Paracetamol + codeine 4/40

AE and LoE:
Ketorolac 3/34
Paracetamol+ codeine 0/40

Other medical problems
Ketorolac 2/34
Paracetamol + codeine 1/40

Minotti 1989

See above

Rodriguez 1994

Dipyrone 3 x 1000 mg daily, n = 41
Dipyrone 3 x 2000 mg daily, n = 38
Morphine 6 x 10 mg daily, n = 42

Dose could be increased on day 4: up to 3 x 2000 mg dipyrone, and 6 x 30 mg morphine

Dipyrone 3000 mg 17/41
Dipyrone 6000 mg 21/38
Morphine 60 mg 14/42

Any AE:
Dipyrone 3000 mg 27/41
Dipyrone 6000 mg 25/38
Morphine 34/42

Incidence and severity lower with dipyrone than morphine, but not statistically significant

Tolerability good, excellent:
Dipyrone 3000 mg 77% (32/41)
Dipyrone 6000 mg 62% (20/38)
Morphine 60 mg 49% (20/42)

SAE: none reported

Somnolence:

Dipyrone 3000 mg 4/41

Dipyrone 600 mg 9/38

Morphine 18/42

Anorexia:

Dipyrone 3000 mg 0/41

Dipyrone 600 mg 0/38

Morphine 1/42

Dyspepsia:

Dipyrone 3000 mg 0/41

Dipyrone 600 mg 1/38

Morphine 1/42

No AE withdrawals

AE: adverse event; GIH: gastrointestinal haemorrhage; LoE: lack of effect; Na: sodium; SAE: serious adverse event

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

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'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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NSAID for cancer pain ‐ non‐controlled data

Patient or population: people with cancer pain

Settings: inpatient or outpatient

Intervention: any NSAID, and dose

Comparison: no control ‐ cohort of treated participants

Outcomes

Probable outcome with NSAID

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Participants with at least 30% or at least 50% reduction in pain

No data

No data

Very low

Limited data, several risks of bias

PGIC much or very much improved

No data

No data

Very low

Limited data, several risks of bias

Pain no worse than mild at one or two weeks (or equivalent)

Range of estimates from 260 in 1000 to 510 in 1000

4 studies

415 participants randomised

Very low

Limited data, several risks of bias

Serious adverse events

2 serious adverse events reported

11 studies

949 participants

Very low

Limited data, several risks of bias

Adverse events

Dry mouth 10%

Loss of appetite 4%

Somnolence 9%

Dyspepsia 9%

Variously reported in studies

Very low

Limited data, several risks of bias

Withdrawals

All cause 23%

Lack of efficacy 24%

Adverse event 5%

Variously reported in studies

Very low

Limited data, several risks of bias

Death

22 deaths, not clearly related to treatment

11 studies

949 participants

Very low

Limited data, several risks of bias

Descriptors for levels of evidence (EPOC 2015):
High quality: This research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different† is low.
Moderate quality: This research provides a good indication of the likely effect. The likelihood that the effect will be substantially different† is moderate.
Low quality: This research provides some indication of the likely effect. However, the likelihood that it will be substantially different† is high.
Very low quality: This research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different† is very high.

† Substantially different: a large enough difference that it might affect a decision.

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